a study to evaluate the effect of multiple doses of jnj-56021927 on the pharmacokinetics of multiple cytochrome p450 and transporter substrates in participants with castration-resistant prostate cancer

Conditions: Prostatic Neoplasms, Castration-Resistant

Summary: the purpose of this study is to evaluate the effects of repeat dosing of jnj-56021927 on the pharmacokinetics for single-dose multiple cytochrome p450 (cyp450) enzymes (cyp3a4, cyp2c9, cyp2c19, cyp2c8) and transporter (p-gp and brcp) substrates in participants with castration-resistant prostate cancer (crpc).

this is a phase 1, multicenter, open-label study in participants with crpc. the study will consist of a screening phase to determine eligibility, a pretreatment phase, a treatment phase, and a follow-up phase. the study is designed to estimate the magnitude of the effects of jnj-56021927 on the pharmacokinetics of probe substrates. in vitro studies have indicated that jnj-56021927 and its active metabolite jnj-56142060 (m3) have the potential to affect multiple cytochrome p450 (cyp) enzymes (cyp3a4, cyp2c9, cyp2c19, and cyp2c8) and drug transporters proteins (p-glycoprotein \[p-gp\] and breast cancer resistance protein \[brcp\]) via inhibition or induction. in human hepatocytes, jnj 56021927 and jnj-56142060 (m3) were found to be inducers of cyp3a4. the induction of cyp3a4 suggests that jnj-56021927 and m3 will induce other cyp isozymes and drug transporters (eg, cyp2c and p-gp via activation of pregnane x receptor). the study is designed to confirm the in vivo significance of these non-clinical findings.

Eligibility criteria:
inclusion criteria: * eastern cooperative oncology group (ecog) performance status score of 0, 1, or 2 * adenocarcinoma of the prostate * participants with non-metastatic castration-resistant prostate cancer (nm-crpc) or metastatic castration-resistant prostate cancer (mcrpc), who in the opinion of the investigator may benefit from treatment with jnj-56021927 * surgically or medically castrated, with testosterone levels of \<50 nanogram per deciliter (ng/dl) * if the participant is being treated with a gonadotropin-releasing hormone (gnrha) (ie, participant who has not undergone bilateral orchiectomy), then this therapy must have been initiated at least 4 weeks prior to the cycle 1 day 1 visit and must be continued throughout the study * adequate bone marrow and organ function defined as: hemoglobin (\>=9.0 g/dl, independent of transfusion or growth factor support within the prior 7 days); absolute neutrophil count (\>=1000/mm\^3 independent of growth factor support within the prior 7 days); platelet count (\>=75,000/mm\^3 independent of transfusion or growth factor support within the prior 7 days); serum albumin (\>=3.0 g/dl); serum creatinine (\ =50 ml/min/1.73m\^2); total bilirubin \[\ =80% of total bilirubin\]); aspartate aminotransferase or alanine aminotransferase (\<=3.0\*uln); prothrombin time (pt) or partial thromboplastin time (ptt) or international normalized ratio (inr) (pt \<=15 sec or inr \<=1.2 ptt \<=40 sec). exclusion criteria: * known brain metastases * chemotherapy or immunotherapy for the treatment of prostate cancer within 4 weeks of the study day 15 (cycle 1 day 1) visit * prior treatment with enzalutamide within 8 weeks before first dose of drug probes * therapies that must be discontinued or substituted prior to study visit day 1, or must be temporarily interrupted during the course of the study, include the following: a) medications known to lower the seizure threshold within 4 weeks before study day 15 (cycle 1 day 1) and b) medications known to induce or inhibit drug metabolizing enzymes (cyp3a4, cyp2c9, cyp2c19 and cyp2c8) or transporter proteins (p-gp, brcp, oatp1b1, and oatpb3) * participant has known allergies, hypersensitivity, or intolerance to any of the study drugs/drug probes or excipients * history of seizure or any condition that may predispose to seizure within 12 months prior to enrollment (study day 1); brain arteriovenous malformation; or intercranial masses such as schwannoma or meningioma that is causing edema or mass effect * participants with poor metabolizer genotype for cyp2c9 (\*2, \*3), or cyp2c19 (\*2, \*3, \*4, \*8)

Keywords: jnj-56021927 prostatic neoplasms, castration-resistant